Glial cells release molecules that influence brain development, function, and disease. Calcium-dependent exocytosis has been proposed as potential release mechanism in astroglia, but the physiological relevance of "gliotransmission" in vivo remains controversial. We focused on the impact of glial exocytosis on sensory transduction in the retina. To this end, we generated transgenic mice to block exocytosis by Cre recombinase-dependent expression of the clostridial botulinum neurotoxin serotype B light chain, which cleaves vesicle-associated membrane protein 1-3. Ubiquitous and neuronal toxin expression caused perinatal lethality and a reduction of synaptic transmission thus validating transgene function. Toxin expression in Müller cells inhibited vesicular glutamate release and impaired glial volume regulation but left retinal histology and visual processing unaffected. Our model to study gliotransmission in vivo reveals specific functions of exocytotic glutamate release in retinal glia.
BackgroundDespite their widespread use, the biological mechanisms underlying the efficacy of psychotropic drugs are still incompletely known; improved understanding of these is essential for development of novel more effective drugs and rational design of therapy. Given the large number of psychotropic drugs available and their differential pharmacological effects, it would be important to establish specific predictors of response to various classes of drugs.ResultsTo identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (using 324 Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8 h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at http://www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found.ConclusionsThe comparison of gene expression alterations between various drugs opened a new means to classify the different psychoactive compounds and to predict their cellular targets; this is well exemplified in the case of tianeptine, an antidepressant with unknown mechanisms of action. This work represents the first proof-of-concept study of a molecular classification of psychoactive drugs.
Stress elicits the release of glucocorticoids (GCs) that regulate energy metabolism and play a role in emotional memory. Astrocytes express glucocorticoid receptors (GR), but their contribution to cognitive effects of GC’s action in the brain is unknown. To address this question, we studied how astrocyte-specific elimination of GR affects animal behavior known to be regulated by stress. Mice with astrocyte-specific ablation of GR presented impaired aversive memory expression in two different paradigms of Pavlovian learning: contextual fear conditioning and conditioned place aversion. These mice also displayed compromised regulation of genes encoding key elements of the glucose metabolism pathway upon GR stimulation. In particular, we identified that the glial, but not the neuronal isoform of a crucial stress-response molecule, Sgk1, undergoes GR-dependent regulation in vivo and demonstrated the involvement of SGK1 in regulation of glucose uptake in astrocytes. Together, our results reveal astrocytes as a central element in GC-dependent formation of aversive memory and suggest their relevance for stress-induced alteration of brain glucose metabolism. Consequently, astrocytes should be considered as a cellular target of therapies of stress-induced brain diseases.
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